Systems and methods are disclosed for forming a pontic in a polymeric shell dental appliance, including providing a polymeric shell dental appliance of the type which is removably placeable over a patient""s dentition, said shell having a concave trough which conforms to the teeth when the appliance is placed over the dentition and a location in the trough corresponding to a missing tooth; and depositing a flexible, durably affixed material in the location to form the pontic.

1. Field of the Invention
This invention relates in general to orthodontics and more particularly to methods and kits for for providing pontics in orthodontic appliances.
2. Description of the Background Art
Orthodontic treatments involve repositioning misaligned teeth and improving bite configurations for improved cosmetic appearance and dental function. Repositioning teeth is accomplished by applying controlled forces to the teeth over an extended period of time. This is conventionally accomplished by wearing what are commonly referred to as xe2x80x9cbraces.xe2x80x9d Braces comprise a variety of appliances such as brackets, bands, archwires, ligatures, and O-rings. After they are bonded to the teeth, periodic meetings with the orthodontist are required to adjust the braces. This involves installing different archwires having different force-inducing properties or by replacing or tightening existing ligatures. Between meetings, the patient may be required to wear supplementary appliances, such as elastic bands or headgear, to supply additional or extraoral forces.
Although conventional braces are effective, they are often a tedious and time-consuming process requiring many visits to the orthodontist""s office. Moreover, from a patient""s perspective, they are unsightly and uncomfortable. Consequently, alternative orthodontic treatments have developed. A particularly promising approach relies on the use of elastic positioning appliances for realigning teeth. Such an appliance may be comprised of a thin shell of elastic material, referred to as an xe2x80x9calignerxe2x80x9d that generally conforms to a patient""s teeth but is slightly out of alignment with the initial tooth configuration. Placement of an aligner over the teeth applies controlled forces in specific locations to gradually move the teeth into the new configuration. Repetition of this process with successive appliances comprising new configurations eventually moves the teeth through a series of intermediate arrangements to a final desired arrangement. A full description of an exemplary elastic polymeric positioning appliance is described in U.S. Pat. No. 5,975,893, and in published PCT application WO 98/58596 which designates the United States and which is assigned to the assignee of the present invention. Both documents are incorporated by reference for all purposes.
Systems of preformed aligners employing technology described in U.S. Pat. No. 5,975,893, are commercially available from Align Technology, Inc., Santa Clara, Calif., under the tradename Invisalign(copyright) System. Align Technology, Inc., is the assignee of the present application. The Invisalign(copyright) System relies on designing and fabricating the aligners to be worn by the patient throughout treatment. The design of the aligners relies on computer modeling of a series of successive tooth arrangements, and the individual aligners are designed to be worn over the teeth and to reposition the teeth to each of said tooth arrangements. Usually, the set of aligners which is designed and fabricated at the outset of the treatment is able to successfully reposition the teeth to a final desired arrangement.
With the Invisalign(copyright) System, as well as with other conventional orthodontic treatment systems, it is sometimes necessary to extract one or more teeth prior to tooth repositioning. At present, the Invisalign(copyright) System does not provide for filling in the space or void which remains within the aligner after the tooth is extracted with a structural component such as an artificial tooth which is commonly referred to as a dental pontic.
The design and fabrication of dental pontics are described in U.S. Pat. Nos. 6,186,790; 6,050,820; 6,049,743 and 5,613,845, the full disclosures of which are incorporated herein by reference. Currently, dental professionals trained in the use of the Invisalign orthodontic system are using a variety of materials and techniques known in the art to fabricate dental pontics which can be worn in the aligner extraction site(s). The most commonly employed materials are tooth-shaded dental composites typically used to repair carious lesions or fabricate provisional (temporary) crowns and bridges. These materials consist mainly of a polymer matrix and dispersed reinforcing inorganic filler particles. Typical polymers used are based on dimethacrylate such as Bis-GMA or urethane dimethacrylate (UDMA). Quartz, lithium aluminum silicate and barium, strontium, or zinc glasses have been commercially distributed as fillers. Typically these materials are packaged as a two-paste (base/catalyst) system. The polymer matrix may be visible light curable, self-curing, dual curing, and vacuum, heat and pressure curable compositions as well as any combination thereof. A popular method for mixing and dispensing these materials involves the use of an automix system whereby a dispensing gun is utilized to dispense the base and catalyst, which are in separate cartridges, through a mixing cannula directly into the extraction site. Commercial examples of the autopolymerizing composites are Luxatemp Plus (DMG/Zenith), Integrity (Dentsply/Caulk), Protemp Garant (ESPE) and Turbo Temp (Danville Engineering). Alternatively light cured composites may be used to fabricate dental pontics. Commercial examples of light cured composites are Revolution (Kerr), Star-Flow (Danville Engineering), and Tetric (Vivadent). Other useful dental composite materials are based on the methyl methacrylate polymer. Such acrylic polymers are well known and commercially available for example as Jet Tooth Shade self-curing acrylic resin by Lang Dental.
Although dental composites have been used to fabricate dental pontics for the Invisalign system there remain two important disadvantages to using these materials. First the ability of these materials to bond to the aligner thermoplastic is poor and second these materials are very stiff and non-flexing. These characteristics significantly compromise retention of the pontic in the aligner especially if it is subjected to torsional or flexing forces such as when the aligner is either being inserted or removed from a patient""s mouth or while the patient is cleaning their aligner using a cleaning device such a toothbrush or denture brush.
While it has been proposed to paint or color a portion of the aligner which overlies the void (see co-pending application Ser. No. 09/454,278, the full disclosure of which is incorporated herein by reference), partial coloring of the aligner can affect the light transmitting properties and be unaesthetic and the lack of any underlying structure can weaken or lessen the resilience of the aligner and limit its effectiveness.
For these reasons, it would be desirable to provide methods, systems, and kits for modifying an aligner to accommodate patients who have had teeth extracted prior to treatment with an aligner or other polymeric shell orthodontic appliance. It would be particularly desirable if the methods would permit an orthodontist or other clinician to modify an aligner or other orthodontic appliance in the professional office, rather than having the modification done at the time of fabrication or at an off-site location. It would be further desirable still if the aligner could be modified by the treating clinician, fitted with the patient, and further modified if necessary for patient comfort or other reasons. The resulting modified aligners or other orthodontic appliances should be esthetically pleasing, and preferably should mask the absence of an underlying tooth while the aligner or other appliance is worn. At least some of these objectives will be achieved by the inventions described hereinafter.
U.S. Pat. No. 5,975,893, and published PCT application WO98/58596, have been described above. Co-pending application Ser. No. 09/454,278, which has been published as WO99/028,228, relates to the fabrication of aligners which have been colored to cover a void left where teeth have been removed. The full disclosures of each of these patents and pending applications are incorporated herein by reference.
The present invention provides methods and kits for forming a pontic in a polymeric shell dental appliance, such as the Invisalign(copyright) System aligners described above. In addition, the present invention provides for methods of using such modified aligners for treating patients having gaps between adjacent teeth, where the gaps resulted from prior tooth extractions or other causes. In addition to the esthetic improvement, i.e., the voids or empty spaces between teeth will be generally invisible, it is believed that the pontics may reduce the tendency of teeth to collapse inward toward each other as the teeth are moved to close the gaps during the orthodontic treatment. In the case of the Invisalign(copyright) System, successive aligners which are used to treat an individual patient can each be separately modified, with the pontic placed in a gap between adjacent teeth being reduced in size as the treatment progresses and the gap is gradually closed.
According to a first aspect of the present invention, a method for forming a pontic in a polymeric shell dental appliance, such as an Invisalign(copyright) System aligner, comprises providing a polymeric shell dental appliance of the type which is removably placeable over a patient""s dentition. The shell will have a concave trough or cavity which conforms to the teeth when the appliance is placed or worn over the dentition. When the polymeric shell is worn, the treating clinician can determine the location in the appliance trough where a tooth is missing. The treating clinician will usually note the location on the appliance and further determine the width and shape of the gap between the teeth. Optionally, in the case of the Invisalign(copyright) System aligners, the aligner will have been shaped or otherwise modified to indicate the location where the gap will occur. If not, the treating clinician can simply mark the aligner or take other appropriate steps to determine the location of the space within the trough.
After the space (or spaces) is determined, the pontic is formed by filling the spaces(s) within the trough with a material that resembles a tooth. While it would be possible to shape a cured material into the desired geometry to be placed within the appliance trough, it will be much more convenient to fill the location with a relatively viscous but flowable and flexible material which can fill and conform to the interior volume of the target location within the appliance trough. Optionally, an adhesive or other treating material will be coated on the target location prior to filling with the pontic material. The flowable pontic material will then be cured to form the final pontic. Optionally, the shape of the pontic can be modified using spatulas (while it is still workable) and/or knives (after it has cured). Preferably, the pontic will be shaped so that it fills substantially the entire gap between adjacent teeth and extends down to the gingiva, without intruding upon the gingiva when the aligner or other appliance is worn.
In a specific embodiment of the present invention, curable silicone compositions, especially the addition-curable silicone rubber compositions known in the art are employed to form an elastomeric, flexible polyvinylsiloxane (PVS) dental pontic. Typically these polyvinylsiloxane materials are formed from a two component curable silicone prepolymer system. A first component, which is referred to as a xe2x80x9cBase Pastexe2x80x9d, typically contains a vinylorganopolysiloxane dispersion, an organo hydrogen-polysiloxane, inorganic fillers and other additives well known in the art. The second component of this two-part composition is referred to as a xe2x80x9cCatalyst Pastexe2x80x9d and typically consists of a second portion of the vinyl polysiloxanes, polymerization initiators, accelerators, cross-linking agents and other additives well known in the art. The base and catalyst may either be hand mixed and delivered to the appliance trough using a spatula or application syringe or a mixing device such as an auto-mix cartridge commonly used for impression materials may be employed to combine the proper volumes of base and catalyst. The tip size of the nozzle can be selected to provide a desired ribbon of material to be delivered to the appliance trough. Preferably, the tip of the nozzle will be held beneath the surface of the PVS as it is being dispensed within the appliance trough. By providing applicators having different tip diameters, the size of the material ribbon and the pontic can be selected by the treating physician.
Another class of curable silicone rubbers useful in forming elastomeric dental pontics are the condensation reaction silicones. Condensation silicones are supplied as either a paste and liquid or as two pastes. Typically the base paste consists of a silicone polymer with terminal hydroxy groups and a filler and the catalyst paste consists of a cross-linking agent (organohydrogen siloxane) and an activator such as dibutyl-tin dilaurate. On mixing the two pastes react by a condensation reaction causing cross-linking. Typically the setting reaction produces a gas such as hydrogen or an alcohol.
Prior to delivering the curable silicone rubber, an adhesive is applied to the aligner segment corresponding to the site of the missing tooth to enhance the bond between the PVS pontic and aligner thermoplastic.
After sufficient material has been dispensed to form the pontic, the treating clinician may optionally shape or form the pontic as desired, typically using conventional shaping tools, such as spatulas. The material will then be cured. In the case of PVS, curing will typically occur after five to ten minutes at room temperature but anybody skilled in the art can vary the material composition to allow for curing times  less than 60 seconds or as long as 24 hours. If it is desired to expedite curing, the PVS material may be gently warmed, e.g., held under a warm water stream. After curing, shaping or trimming of the pontic may be performed using a knife, abrasive instrument, or the like.
Non-toxic, inorganic iron oxide pigments may be incorporated in the PVS polymer to provide for a tooth-colored shade for the finished pontic. Optionally, a range of tooth-colored PVS resins may be provided in a kit allowing the clinician to select a color that best matches patient""s teeth. In a second aspect of the present invention, kits are provided comprising components of the system useful for performing the methods described above. In particular, the basic kit would include a curable, toothshaded PVS resin material such as described above in combination with instructions for use setting forth a method for forming the pontic within the trough of an aligner or other thin polymeric appliance having a trough or cavity which is removebly placed over teeth. In particular, the instructions will set forth a first step of determining the location in the trough where a tooth is missing from the patient""s dentition, and a second step comprising filling the location with the filler so that the material resembles a tooth when the location is filled.
Optionally, the kit may further include other components, such as an adhesive for coating an interior surface of the appliance trough at the location to be filled. When an adhesive is supplied, the kit will typically also include a brush, sprayer, or other applicator for applying the adhesive to the appliance trough. The kit may still further comprise one or more nozzles for use with a filler applicator for dispensing the curable filler material within the appliance trough. Typically, the filler applicator will be a dispensing gun capable of applying the PVS resin in a controlled manner through the nozzle which is attached to the gun. More typically, the kit will include two or more nozzles, where each nozzle will have a different tip diameter to dispense a different ribbon size of the filler to most efficiently fill target locations of differing sizes. Further optionally, the kit may include two or more cartridges or other containers of the curable filler material, where the materials have different properties, such as color. Still further optionally, the kit could include one or more coloring materials to permit the clinician to mix and color the filler material at the time of use. In addition, the kit may include one or more shaping tools which permit precise sizing and shaping of the pontic. For example, the kit may be provided with a spatula for sizing and shaping the material before it is cured. Alternatively or additionally, the kit may comprise a knife, grinder, or other tool for shaping and removing the filler material after it has cured. To facilitate the fabrication of dental pontics in a manufacturing setting, the curable tooth-colored silicone rubber catalyst- and base-paste may be supplied in foil bags and precisely dispensed from a Pentamix system eliminating either hand-mixing or dispensing with a hand held dispensing gun.
In a third aspect of the present invention, improved methods for repositioning teeth after extractions or impatience with substantial gaps between adjacent teeth are provided. The improvements are in methods for repositioning teeth which use polymeric shell appliances each of which have a trough for receiving and resiliently repositioning the teeth, e.g., as in the Invisalign(copyright) System commercially available from Align Technology, Inc., assignee of the present application. The polymeric shell appliances have different geometries and are worn successively by a patient to reposition the teeth in a number of stages. The improvement comprises providing at least some of the polymeric shell appliances, also referred to as aligners, which have pontics at a location within the appliance trough which will fill a gap between teeth when the appliance is worn. Usually, each appliance worn will have a pontic at the location of the gap, and the size of the pontic may be decreased as the treatment progresses and the width of the gap closes. In addition to the esthetic benefits described above, the provision of a pontic within the gap as the teeth are being closed is believed to provide therapeutic benefits as well. In particular, the presence of the pontic will reduce or eliminate the tendency of teeth which are being closed over a gap to tilt or incline into the gap. Thus, it is expected that teeth which are treated with the polymeric appliances to close such gaps will remain generally more upright as they are moved, thus reducing or eliminating the need to correct any tilt or inclination which is induced by the treatment.

Method and kits for forming pontics in polymeric shell aligners


This relates to procedures and to devices for treating cardiac tissue by forming lesions in that tissue using photodynamic therapy techniques. In particular, the procedure is valuable for rectifying various cardiac arrhythymias with those so-formed lesions. Central to this procedure is the delivery of light to the desired lesion site in cooperation with delivery of a photodynamic drug to that site. The invention also relates to devices, particularly catheters, that are suitable for delivering the light for forming those lesions.

This invention relates to procedures and to devices for treating cardiac tissue by forming lesions in that tissue using photodynamic therapy techniques. In particular, the procedure is valuable for rectifying various cardiac arrhythymias with those so-formed lesions. Central to this procedure is the delivery of light to the desired lesion site in cooperation with delivery of a photodynamic drug to that site. The invention also relates to devices, particularly catheters, that are suitable for delivering the light for forming those lesions.
Many abnormal medical conditions in humans and other mammals have been associated with disease and other aberrations along the lining or walls of blood vessels. Treatment of such abnormal wall conditions has included various medical device technologies that deliver various forms of energy to specific regions of vascular wall tissue.
For instance, atherosclerosis, a vascular disease characterized by abnormal deposits upon vessel walls or the thickening of those walls, is an example of an abnormal wall condition. The dangers related to flow blockages or functional occlusions resulting from the disease have made atherosclerosis the focus of many medical devices. Such devices are often categorized by structure and tissue treatment mechanism. The categories include direct contact electrode devices, resistance heating devices, light transmission devices, light-to-heat conversion devices, hot fluid devices, and radio frequency (RF) heated devices.
The first category includes a variety of contact electrode devices. For instance, U.S. Pat. No. 4,998,933, to Eggers et al, describes a catheter for thermal angioplasty using a heated electrode in direct contact with surrounding tissue or plaque deposits. The heated electrode serves to treat the diseased lumen walls. U.S. Pat. No. 4,676,258, to Inokuchi et al, and U.S. Pat. No. 4,807,620, to Strul et al, disclose devices designed to treat surrounding tissues using heat generated by two electrodes within the device and an RF power source.
U.S. Pat. No. 4,672,962, to Hershenson, and U.S. Pat. No. 5,035,694, to Kasprzyk et al, disclose devices which may be categorized as resistance heating probes. In each of these devices, current flowing through a conductive material at the end of the device provides heat that is transmitted to surrounding tissues for treatment of atherosclerosis and other diseases. Current is transmitted in each of these devices by electrically conductive materials. In contrast, U.S. Pat. No. 5,226,430, to Spears et al, discloses a device which uses light transmitting fiber to transmit energy to a heat generating element at the tip of the device. That heat generating element in turn transmits heat energy to a surrounding balloon structure which is in contact with surrounding tissue. Similarly, U.S. Pat. No. 4,790,311, to Ruiz, discloses an angioplasty catheter system having heat generating electrode at the tip of the device that is heated using RF energy. This device may be categorized as an RF heated device.
U.S. Pat. Nos. 5,190,540 and 5,292,321, to Lee, describe hot fluid-containing devices. Lee ""540 shows a balloon catheter designed for remodeling a body lumen. This catheter uses a multilumen shaft that delivers a heated fluid to an expandable balloon. The expanded balloon heats the tissue that is in contact with the expanded balloon. Lee ""321 shows a somewhat similar device. However, the expandable balloon is instead filled with a selected thermoplastic material that becomes softer and more compliant when heated by a heating element.
Diseased or structurally damaged blood vessels often involve various abnormal wall conditions. The inducement of thrombosis and control of hemorrhaging within such vessels have been the focus of several devices that use catheter-based heat sources for cauterizing damaged tissues. U.S. Pat. No. 4,449,528, to Auth et al, discloses a thermal cautery probe designed for heating specific layers of tissue without producing deep tissue damage. The mechanism of heat generation in this device is a resistive coil within the cautery probe that is electrically connected to a power source. U.S. Pat. No. 4,662,368, to Hussein et al, discloses a device designed for localized heat application within a lumen; In this device, energy in the form of light is delivered to the tip of the device for heat generation, by a flexible fiber. Heat from an element that converts light energy to heat energy passes to the adjacent tissue.
Although there are a variety of devices that deliver energy to vascular lumena, none of them deliver the energy in the form of light which cooperatively forms lesions in cardiac tissue using photodynamic chemicals to treat that cardiac tissue and to prevent various forms of fibrillation.
Cardiac arrhythmias, and atrial fibrillation in particular, are common, dangerous medical ailments, particularly in the aging population. In patients with normal sinus rhythm, the heart, which is made up of atrial, ventricular, and excitatory conduction tissue, is electrically excited to beat in a synchronous, patterned fashion. In patients with cardiac arrhythmia, regions of cardiac tissue do not follow the synchronous beating cycle associated with normally conductive tissue in patients with sinus rhythm. Instead, the abnormal regions of cardiac tissue aberrantly conduct to adjacent tissue, thereby disrupting the cardiac cycle into an asynchronous cardiac rhythm. Such abnormal conduction generally occurs at various, specific regions of the heart, for example: in the region of the sino-atrial (SA) node, along the conduction pathways of the atrioventricular (AV) node and the Bundle of His, or in the cardiac muscle tissue forming the walls of the ventricular and atrial cardiac chambers.
Cardiac arrhythmias, including atrial arrhythmia, may be of a multiwavelet re-entrant type, characterized by multiple asynchronous loops of electrical impulses that are scattered about the atrial chamber. These arrhythmias are often self propagating. Cardiac arrhythmias may also have a focal origin, such as when an isolated region of tissue in an atrium fires autonomously in a rapid, repetitive fashion. Cardiac arrhythmias, including atrial fibrillation, may be detected using the global technique of an electrocardiogram (EKG). More sensitive procedures of mapping the specific conduction along the cardiac chambers have also been disclosed, such as for example in U.S. Pat. No. 4,641,649 to Walinsky et al and WO 96/32897 to Desai.
A variety of clinical conditions may result from the irregular cardiac function and resulting hemodynamic abnormalities associated with atrial fibrillation, including stroke, heart failure, and other thromboembolic events. Atrial fibrillation is believed to be a significant cause of cerebral stroke; the abnormal hemodynamics in the left atrium caused by the fibrillatory wall motion precipitate the formation of thrombus within the atrial chamber. A thromboembolism is ultimately thrown off into the left ventricle, which then pumps the embolism into the cerebral circulation causing a stroke. For these reasons, there are a number of procedures for treating atrial arrhythmias.
Conventional Atrial Arrhythmia Treatments
There are several pharmacological approaches intended to remedy or otherwise treat atrial arrhythrnias. See. for example, U.S. Pat. No. 4,673,563, to Beme et al; U.S. Pat. No. 4,569,801, to Molloy et al; and Hindricks, et al in xe2x80x9cCurrent Management of Arrhythmiasxe2x80x9d (1991). However, such pharmacological solutions are not always effective and may in some cases result in proarrhythmia and long term inefficacy.
Several surgical approaches have been developed to treat atrial fibrillation. One example is known as the xe2x80x9cmaze procedure,xe2x80x9d as is disclosed by Cox, J. L. et al in xe2x80x9cThe surgical treatment of atrial fibrillation. I. Summaryxe2x80x9d Thoracic and Cardiovascular Surgery 101(3), pp. 402-405 (1991); and also by Cox, J. L. in xe2x80x9cThe surgical treatment of atrial fibrillation. IV. Surgical Techniquexe2x80x9d, Thoracic and Cardiovascular Surgery 101(4), pp. 584-592 (1991). In general, the xe2x80x9cmazexe2x80x9d procedure is designed to relieve atrial arrhythmia by restoring effective atrial systole and sinus node control via a specific pattern of incisions in the tissue wall. Early on, the xe2x80x9cmazexe2x80x9d procedure included surgical incisions in both the right and the left atrial chambers. However, more recent reports predict that the surgical xe2x80x9cmazexe2x80x9d procedure may be effective when performed only in the left atrium. See, Sueda et al, xe2x80x9cSimple Left Atrial Procedure for Chronic Atrial Fibrillation Associated With Mitral Valve Diseasexe2x80x9d (1996).
The xe2x80x9cmaze procedurexe2x80x9d as surgically performed in the left atrium generally includes forming vertical incisions from the two superior pulmonary veins and terminating in the region of the mitral valve annulus, traversing the inferior pulmonary veins en route. An additional horizontal incision also connects the superior ends of the two vertical incisions. The atrial wall region bordered by the pulmonary vein ostia is therefore isolated from the other atrial tissue. In this way, the mechanical sectioning of atrial tissue eliminates the precipitating conduction to the atrial arrhythmia by creating conduction blocks within the aberrant electrical conduction pathways.
Although the xe2x80x9cmazexe2x80x9d procedure is generally effective, it is a highly invasive procedure. Nevertheless, the procedures have provided a guiding principle for alleviating arrhythmia: the mechanical isolation of faulty cardiac tissue often prevents atrial arrhythmia, and particularly atrial fibrillation caused by perpetually wandering reentrant wavelets or focal regions of arrhythmogenic conduction.
Modern Catheter Treatments for Atrial Arrhythmia
Success with surgical interventions through atrial segmentation, particularly with regard to the surgical xe2x80x9cmazexe2x80x9d procedure just described, has caused others to develop less invasive catheter-based approaches to treat atrial fibrillation through cardiac tissue ablation. Examples of such catheter-based devices and treatment methods have generally targeted atrial segmentation with ablation catheter devices and methods adapted to form linear or curvilinear lesions in the wall tissue which defines the atrial chambers, such as are disclosed in the following: U.S. Pat. No. 5,617,854, to Munsif; U.S. Pat. No. 4,898,591, to Jang et al; U.S. Pat. No. 5,487,385, to Avitall; and U.S. Pat. No. 5,582,609 to Swanson.
Additional examples of catheter-based tissue ablation in performing less-invasive cardiac chamber segmentation procedures are also disclosed in the following articles: xe2x80x9cPhysics and Engineering of Transcatheter Tissue Ablationxe2x80x9d, Avitall et al., Journal of American College of Cardiology, Volume 22, No. 3:921-932 (1993); and xe2x80x9cRight and Left Atrial Radiofrequency Catheter Therapy of Paroxysmal Atrial Fibrillation,xe2x80x9d Haissaguerre, et al., Journal of Cardiovascular Electrophysiology 7(12), pp. 1132-1144 (1996).
Furthermore, various energy delivery modalities (microwave, laser, and more commonly, RF) is used to create conduction blocks (atrial wall lesions) along the cardiac tissue wall. See, WO 93/120767, to Stem et al; U.S. Pat. No. 5,104,393, to Isner et al; and U.S. Pat. No. 5,575,766, to Swartz et al.
Additionally, ablation catheter devices and methods have also been used to ablate arrhythmogenic tissue of the left-sided accessory pathways, such as those associated with the Wolff-Parkinson-White syndrome, through the wall of an adjacent region along the coronary sinus.
For example, Fram et al, in xe2x80x9cFeasibility of RF Powered Thermal Balloon Ablation of Atrioventricular Bypass Tracts via the Coronary Sinus: In vivo Canine Studies,xe2x80x9d PACE, Vol. 18, p 1518-1530 (1995), discloses attempted thermal ablation of left-sided accessory pathways in dogs using a balloon which is heated with bipolar radiofrequency electrodes positioned within the balloon. Fram et al suggests that the lesion depth of some population groups may be sufficient to treat patients with Wolff-Parkinson-White syndrome.
Additional examples of cardiac tissue ablation from the region of the coronary sinus for the purpose of treating particular types of cardiac arrhythmias are disclosed in: xe2x80x9cLong-term effects of percutaneous laser balloon ablation from the canine coronary sinusxe2x80x9d, Schuger CD et al., Circulation (1992) 86:947-954; and xe2x80x9cPercutaneous laser balloon coagulation of accessory pathwaysxe2x80x9d, McMath L P et al., Diagn. Ther. Cardiovasc. Interven. 1991; 1425:165-171.
Focal Arrhythmias Originating from Pulmonary Veins
Atrial fibrillation may be focal in nature, caused by the rapid and repetitive firing of an isolated center within the atrial cardiac muscle tissue. These foci, defined by regions exhibiting a concentric pattern of electrical activation, may act either to trigger atrial fibrillation or to sustain the fibrillation. Some studies have suggested that focal arrhythmia often originates from a tissue region along the pulmonary veins of the left atrium, and even more particularly in the superior pulmonary veins.
Less-invasive percutaneous catheter ablation techniques have been disclosed which use end-electrode catheter designs with the intention of ablating and thereby treating focal arrhythmias in the pulmonary veins. These ablation procedures are typically characterized by the incremental application of electrical energy to the tissue to form focal lesions designed to interrupt the inappropriate conduction pathways.
One example of a focal ablation method intended to destroy and thereby treat focal arrhythmia originating from a pulmonary vein is disclosed by Haissaguerre et al, xe2x80x9cRight and Left Atrial Radiofrequency Catheter Therapy of Paroxysmal Atrial Fibrillation,xe2x80x9d Journal of Cardiovascular Electrophysiology 7(12), pp. 1132-1144 (1996). Haissaguerre et al discloses radiofrequency catheter ablation of drug-refractory paroxysmal atrial fibrillation using linear atrial lesions complemented by focal ablation targeted at arrhythrnogenic foci. The site of the arrhythmogenic foci were generally located just inside the superior pulmonary vein.
In another focal ablation example, Jais et al. in xe2x80x9cA focal source of atrial fibrillation treated by discrete radiofrequency ablationxe2x80x9d Circulation 95:572-576 (1997) discusses the use of an RF ablative technique to patients with paroxysmal arrhythmias originating from focal sources variously in both the right and left atria.
None of the cited references discloses a procedure or assembly for creating lesions in cardiac tissue using a light source in cooperation with photoactivatable chemical compounds to form lesions or conduction blocks about focal arrhythmias.
Central to the invention disclosed here is the use of photodynamic therapy (PDT) techniques to create lesions having the same function as those discussed just above. The inventive methods are significantly less invasive; specifically, the lesions may be created without surgery, without the use of any cardiac bypass procedures, and without the use of heat.
There are a variety of medical procedures requiring administration of light or irradiated energy to a patient within the body. One such example is the use of a light activated compound selectively to kill target cells in a patient; as noted above, such therapy is often termed photodynamic therapy (xe2x80x9cPDTxe2x80x9d). In such PDT methods, a light-activated drug is injected into a patient and a targeted light source is used selectively to activate the drug. When activated by light of a proper wavelength, the light-activated drug produces a toxic, often cytotoxic, agent that mediates the destruction of the surrounding cells or tissue.
Currently, the major application of PDT is for the destruction of malignant cell masses. PDT has been used effectively in the treatment of a variety of human tumors and precancerous conditions including basal and squamous cells, skin cancers, breast cancer, metastatic skin cancers, brain tumors, head and neck cancers, stomach cancers, and female genital tract malignancy, cancers and precancerous conditions of the esophagus such as Barrett""s esophagus. A review of the history and progress of PDT is provided by Marcus, S. Photodynamic Therapy of Human Cancer: Clinical Status, Potential, and Needs. In Gomer, C. J. (ed.); xe2x80x9cFuture Directions and Applications in Photodynamic Therapy.xe2x80x9d Bellingham, W. A. SPIE Optical Engineering Press (1990) pp 5-56. Specific applications of PDT are provided by Overholt et al., Sem. Surg. Oncol. 11:1-5 (1995).
The use of various porphyrin compounds as the photoactivated compounds in such treatments is known. These treatments are often tumor-selective in that selected porphyrin compounds accumulate at higher concentrations in tumor tissue than in normal tissue.
In general, the PDT procedure involves administration of a sensitizer compound (such as the porphyrin derivatives) to the target tissue and a subsequent step involving the application of light to that tissue. The PDT procedures function selectively to eradicate diseased tissue in the immediate area of the light source by generating singlet oxygen and activated molecules which damage tissue in that immediate area. Selectivity is attained through the preferential retention of the photosensitizer in rapidly metabolizing tissue such as tumors (Kessel, David, xe2x80x9cTumor Localization and Photosensitization by Derivatives of Hematoporphyrin. A Reviewxe2x80x9d IEEE J. QUANTUM ELECTRON., QE 23(10): 1718-20 (1987)); virally infected cells (J. Chapman et al, xe2x80x9cInactivation of Viruses in Red Cell Concentrates with the Photo Sensitizer Benzoporphyrin Derivative (BPD)xe2x80x9d, TRANSFUSION 31(suppl): 47S Abstract S172, (1991) and J. North et al., xe2x80x9cViral Inactivation in Blood and Red Cell Concentrates with Benzoporphyrin Derivativexe2x80x9d, Blood Cells, 18: 129-140 (1992)); leukaemic cells (C. H. Jamieson, xe2x80x9cPreferential Uptake of Benzoporphyrin Derivative by Leukaemic versus Normal Cellsxe2x80x9d, Leuk. Res. (England) 1990, 14 (3), pp 209-210); psoriatic plaque (M. W. Rems et al, xe2x80x9cResponse of Psoriasis to Red Laser Light (630 nm) Following Systemic Injection of Hematoporphyrin Derivativexe2x80x9d, Lasers Surg Med. 1984, 4(1) pp 73-77); and atherosclerotic plaque (S. Andersson-Engels et al, xe2x80x9cFluorescence Diagnosis and Photochemical Treatment of Diseased Tissue Using Lasers: Part IIxe2x80x9d, Anal. Chem. 62(1), 19A-27A (1990). The activation of the photosensitizer by light occurs only at the site at which the light is present. Obviously, the photo-sensitizer-mediated destruction of tissue occurs only at the desired treatment site. The non-activated photosensitizer is substantially nontoxic and will eventually be cleared from the body.
In a typical PDT treatment, PHOTOFRIN.RTM. porfimer sodium, BPD, or BPD-MA is injected into a patient. See, for instance, Ho et al., xe2x80x9cActivity and Physicochemical Properties of PHOTOFRIN.RTM.xe2x80x9d, Photochemistry and Photobiology, 54(1), pp 83-87 (1991); U.S. Pat. No. 4,866,168, to Dougherty et al. An appropriate dose is, e.g., 0.255-2.5 mg/kg of body weight, depending upon the diseased tissue and the choice of photosensitizer. At an appropriate time after photosensitizer administration, the diseased tissue or site is illuminated with a light source at an appropriate wavelength (630 nm for PHOTOFRIN.RTM. and 690 nm for BPD) to activate the photosensitizer. The light-activated drug induces the formation of singlet oxygen and free radicals which damage the surrounding tissue. Both the diseased tissue and the vasculature feeding it are affected and the unwanted tissue is either directly destroyed or starved of oxygen and nutrients due to the occlusion of blood vessels. After the completion of the PDT, the treated tissue becomes necrotic and will either debride naturally or be debrided by the clinician.
Hematoporphyrin and PHOTOFRIN.RTM. have absorption spectra in the neighborhood of 630 nm. The absorption spectra of much blood and tissue is also in the same general spectral region. Consequently, much of the energy impinging upon the treated tissue is absorbed in the tissue itself, thereby limiting, in a practical sense, the physical depth to which the PDT treatment using hematoporphyrin and PHOTOFRIN.RTM. may be used. BPD-MA has an absorption spectra with peaks in longer wavelength regions, e.g., 690 nm. These compounds are viewed as improvements to the PDT treatment method in that the tissues do not absorb so much of the light energy and therefore allow increased depth of light penetration.
It has been the desire and the practice in PDT treatment to provide uniform illumination in a chosen treatment area.
Allardice et al., Gastrointestinal Endoscopy 35:548-551 (1989) and Rowland et al, PCT application WO 90/00914, disclose a light delivery system designed for use with PDT. The disclosed system involves a flexible tube having a dilator and a transparent treatment window that defines a treatment area by using opaque end-caps made of stainless steel. A fiber optic element that is connected to a laser and ends in a diffusing tip is used in combination with the dilator to deliver light to a tissue source. Allardice et al suggests that the advantages of this apparatus over the use of balloon-type catheter reside in providing a more uniform distribution of light.
Nseyo et al, Urology 36:398-402 (1990) and Lundahl, U.S. Pat. Nos. 4,998,930 and 5,125,925, disclose a balloon catheter device for providing uniform light radiation to the inner walls of hollow organs. The device is a balloon catheter design having a balloon at one end of the apparatus and an optical fiber ending in a diffusion tip that is inserted into the lumen of the balloon through the catheter. The catheter""s centering tube is said to provide a more uniform distribution of the laser light by centering the optical fiber in the inflated balloon. These catheter devices further incorporate optical sensing fibers in the balloon wall to allow measurement of the resulting illumination.
Panjehpour et al, Lasers and Surgery in Medicine 12:631-638 (1992) discloses the use of a centering balloon catheter for esophageal PDT. Panjehpour et al discloses a cylindrical balloon catheter into which a fiber optic probe ending in a light diffuser is inserted.
Overholt et al, Lasers and Surgery in Medicine 14:27-33 (1994) discloses various structures similar to the balloon catheter device described in Panjehpour et al. Overholt et al""s includes a black opaque coating on both ends of the balloon to define a 360xc2x0 treatment window. Overholt et al additionally describes a modified balloon in which one-half of the circumference of the treatment window is rendered opaque to light using the black coating material. This configuration provides a 180xc2x0 treatment window.
Rowland et al, PCT application WO 90/00420, discloses a light-delivery system for irradiating a surface. The device has a hemispherical shell in which the inside is entirely coated with a diffuse reflector. A light source is mounted within the shell. The light source may contain a diffusing source at the tip allowing diffusion of light within the reflective shell.
U.S. Pat. No. 5,344,419, to Spears, discloses devices and methods for making laser-balloon catheters. Spears uses a process that etches an end of a fiber optic cable to provide a diffusion tip on that optical cable. The optical cable containing the etched tip is secured within a central channel of a balloon catheter using a coating of adhesive containing microballoons. The position of the tip within the central channel and the microballoons contained in the adhesive provide increased efficiency in diffusing the laser radiation in a cylindrical pattern, providing uniform illumination at the target site.
U.S. Pat. No. 5,354,293, to Beyer et al, discloses a balloon catheter for delivering light for use in PDT. That balloon catheter employs a conical tipped fiber optic cable for deflecting a light beam radially outward through a transparent portion of an inflated balloon.
Although various of the disclosures discussed above provide ways for providing light to a target site, none of them suggest a procedure for creating lesions in cardiac tissue using PDT, particularly for control of cardiac arrhythymia, nor do they suggest endovascular light-delivery devices that are specifically configured to provide limited lineal or circumferential lesions in cardiac tissue.
This invention relates to methods for producing lesions in cardiac tissue by the step of subjecting cardiac tissue containing a photodynamic drug to a light source in a predetermined pattern to form a lesion corresponding to that predetermined pattern. Normally, the step of forming the lesions is heat-free. The method may also include the step of introducing the photodynarnic drug, locally or systemically, to the cardiac tissue.
Preferably the selected, predetermined pattern is one which limits, controls, or prevents cardiac arrhythymia. Among the preferred predetermined patterns are those which encircle the pulmonary vein bed in the left atrium and those which encircle at least one os of superior pulmonary veins in the left atrium.
The procedure may apply the lesions to the cardiac tissue from the exterior of the heart, e.g., through the epicardium or via a surgical or an endovascular procedure to the interior of the heart.
The preferred light delivery device, i.e., for providing light to the selected cardiac tissue, comprises a generally linear member having a distal region with an axis. That distal region preferably includes a substantially clear and linear light emitting region corresponding to said axis. The light emitting region is preferably bendable to conform to curved cardiac tissue. That light emitting region generally emits all of the light emanating from said device and may be, e.g., a window or lens or at least one LED.

Procedures for photodynamic cardiac ablation therapy and devices for those procedures


Method for recording and transmitting a multi-channel ECG and arrangement as a portable recorder for carrying out the procedure.

The invention belongs to the field of medical technology and relates the reading, recording and transmittance of bioelectrical signals of the body or parts of the same for diagnostic purposes, in so far as it is a method for recording and transmitting a multi-channel ECG and an arrangement as a portable recorder for carrying out this procedure. This procedure and this arrangement is part of a telemedical system (ECGxe2x80x94recorderxe2x80x94mobile telephonexe2x80x94evaluation center) which forms the basis for a mobile ECG monitoring system for high-risk patients.
Equipment for mobile patient monitoring is mainly known in the form of two differing types of devices, and the associated but differing methods.
The first group of devices includes mobile telephones. Representatives of these are, for example, the technical solutions described in patent specifications EP 0 679 041 A2 and DE PS 197 07 681 C1. The technical solution described in patent specification EP 0 679 041 A2 is solely suitable for determining the location of the patient using his positional data. In the case of the technical solution described in the aforementioned patent specification DE PS, the selected medical data is measured by means of special contacts on the mobile telephone which are fifted to the body of the patient or attached by means of wiring and transmitted over the radio communications network, following which immediate aid measures can be taken. Going beyond the simple determination of the position of the patient as described in the aforementioned EP patent specification, here the current data is transmitted immediately, in contrast to the aforementioned EP solution, in order to identify the patient and/or to record the ECG signals. A disclosure of which, that such an aforementioned mobile telephone independently monitors the patient and in a medically significant event automatically transmits the recorded data over the radio communications network, cannot be proven, in particular, but also just because of this reason, cannot be assumed, as an emergency call button on the device which is to be operated by the patient is specified, which the patient himself can or must operate in threatening situations. It must be noted that the disadvantage of these aforementioned technical solutions is that it is not possible to store and record large amounts of relevant data in the case of monitoring measures conducted uninterruptedly over a long period, for several days, weeks or months. An operating facility for transmitting stored and recorded data to a xe2x80x9ccentralxe2x80x9d computer for the purpose of evaluating the time course of the relevant data is also not disclosed. Therefore, in the case of the aforementioned solutions, only the data relating to the normal momentary situation or a special momentary event is transmitted, and not the case history leading up to the event and its subsequent evaluation. Furthermore, these radio telephones differ considerably from conventional devices designed for telephoning, as they are special devices employing special application systems and are for the main part scarcely designed or suitable for conventional telephoning purposes.
The second group of devices includes the recorders. Several types of recorders designed to be worn on the body have become known.
So-called long-term ECG recorders generally record the ECG of the patient continuously, usually over a period of 24 hours, by means of an electronic memory. These recorders with integrated data carriers are then given to the doctor. The data is read out or removed and evaluated at a later time. With so-called event recorders a brief ECG period, usually measured in seconds, is recorded and transmitted in the event of a critical heart event or at predefined intervals. This data is transmitted by telephone using a fixed-network telephone in a complicated procedure. The stored ECG is modulated into an audio frequency enabling it to be transmitted by telephone to an evaluation center.
In the case of so-called event recorders with looping function, an ECG is continuously stored by means of electrodes attached to the body and then repeatedly overwritten after a period of seconds or minutes. If an event occurs the case history immediately prior to the event is herewith stored. The ECG is then transmitted to the evaluation center as in the case of the previous event recorders.
Recently recorders that can be implanted have become known. The internal ECG memory allows data to be stored for up to approximately an hour. The ECG can be read out externally.
The particular disadvantageous technical effects of these aforementioned technical solutions with regard to their arrangement and method characteristics are described below.
Long-term ECG recorders only allow the ECG to be analyzed, and therefore pulse irregularities to be detected, after the data has been recorded. The patient is only monitored for 24 or 48 hours, and control results can only be recognized after a further, considerable delay. Consequently only a diagnosis, also termed a xe2x80x9cfollow-up diagnosisxe2x80x9d, is possible whichxe2x80x94in the case of rare eventsxe2x80x94offers an extremely limited degree of accuracy and which makes the development, for example in the case of medicinal therapy, practically impossible.
Event recorders are designed to circumvent the disadvantage of the xe2x80x9cfollow-up diagnosisxe2x80x9d to as great an extent as possible. ECG events or phases are recorded. However, these are then transmitted to an evaluation center using a complicated and time-consuming procedure, which inherently leads to a reduction in quality and requires a fixed-network telephone with audio frequency modulation. The entire process is extremely difficult to manage, which severely restricts its use in the age group most at risk, if not making it impossible altogether. Furthermore, a real transmission of data is scarcely possible in an emergency situation. The mobility of the patient is restricted by the required fixed-network telephone. The help of a second person is usually required due to the complicated procedure involved, which is very likely to lead to incorrect use under stressful circumstances. Another factor in the case of the first group of recorders is that a brief event is never recorded as the patient himself must first recognize that an event has occurred, and this is then unavoidably only recorded once it has happened. The diagnostic value is therefore extremely limited.
Although implanted recorders require no effort to be operated, they do need to be implanted and must then be replaced after about 1 year. The implantation of a device for diagnostic purposes can only be expected of a small number of very high-risk patients. The costs of an implantation are, of course, very high. Due to their design, implanted devices are only of limited use as event recorders.
The technical solution as described in patent specification DE OS 198 48 229 A1 describes an arrangement for recording and transmitting digitalized medical data for monitoring a patient online, which comprises a data recording component (A) and a xe2x80x9cmobile phone unitxe2x80x9d (B) combined in a single device. ECG data is sent directly to the RAM memory by the analog-to-digital converter and then from here directly to the mobile phone unit. This means that it is not possible to treat and/or control data, for example in the sense of data compression, as is evident from the two single figures in the specification, see directions of the arrows for the signal path. The technical function must be questioned in accordance with the contents of the disclosure of the specification, as it is pointless to save the A/D converted signals 0.1 without storing a quantity of data ordered and managed by a controller properly and system-compatibly in order to then process and/or use it further. Furthermore FIG. 1, as well as FIG. 2, of the patent specification DE OS 198 48 229 does not allow the contents of the memory to be read directly into a computer (PC). The characteristics named and claimed in the principle claim of this patent specification DE OS support this evaluation, as the arrangement characteristics named here are supposed to trigger the procedure characteristics xe2x80x9c. . . to digitalize the analog recording data from the electrodes in the converter, to store it in the electronic memory, and to transmit it from here from the mobile phone unit over a radio communications network . . . xe2x80x9d. In contrast to the facts presented above, a reading out of the memory is described in the specification section in Column 2, Lines 39 to 41, which according to the contents of the disclosure of this specification, however, is not possible with this arrangement. A further disadvantage of the technical solution described in patent specification DE OS 198 48 229 is that only simple pulse rhythm irregularities can be detected using the threshold switches specified here, and that it is not possible to detect critical pulse irregularities, which in turn puts the medical value or the required safety of the patient in question. Finally, it is also a disadvantage that the data acquisition and recording unit, as well as the mobile phone unit, are combined in a single device: it would surely be more practical and also more economical to work with one data acquisition and recording unit and a conventional mobile telephone, rather than possibly having two of the latter, due to the fact that the latter special, and otherwise unusable, mobile phone unit is already included in the technical solution described in patent specification DE OS 198 48 229.
Furthermore, all of this equipment together with the associated procedural processes is not able to record and store ECGs and to transmit them to an evaluation center for immediate processing, generally in computer systems, where necessary with the aid of any commercially available, conventional radio telephone (mobile phone).
Taking into consideration the shortcomings of the state of the art described above and their causes, this invention is based on the purpose of creating a method and an arrangement with which recorded ECGs can be transmitted automatically in any length, as well as triggering an automatic transmission of ECG data in the event of critical pulse irregularities using a (commercially available) conventional mobile telephone, and thereby forming an xe2x80x9cECG transmissionxe2x80x9d complex exploiting the full potential of mobile telephones. A further purpose of the invention should also be to realize such a high memory capacity so that the arrangement allows either discontinuous ECG monitoring over a longer period of days, weeks to months, or continuous ECG monitoring over 48 hours, whereby removal of the storage medium should also be possible. Total mobility of the patient when recording ECGs and during data transmission should also be ensured. This purpose is fulfilled for a generic method and a generic arrangement according to the present invention by the features listed in the characterizing part of the claims 1 to 8.
An arrangement is hereby created which is represented by a portable recorder with the following principal modules: multi-channel amplifier, A/D converter, microcontroller, RAM and flash-ROM memory elements, a removable flash card, pacemaker controller and interface. A mobile telephone unit was intentionally not included in the arrangement according to the invention, as this involves an associated unusable performance in partially restricting special functionality. It was also the aim of the invention to implement according to the present invention universal and commercially available mobile telephones (mobiles), as have already been sold millions of times over, for data communication. Previously known, modern and recent technology for mobile patient monitoring did not take this, economically, very important factor into consideration and always assumed that it would be able to integrate mobile radio telephone technology into such a medical monitoring system in a converted form for its own purposes. The advantages of separating data acquisition and recording from the mobile phone unit are obvious. In addition to simpler assembly and lower work, time, material and cost expenditure during manufacture, marketing and operation (particularly with regard to the weight in the latter case), as otherwise devices would be xe2x80x9cdoubledxe2x80x9d, any type of mobile phone (which is often available anyway) can be used. This technical solution will, of course, always be represented with a mobile telephone according to the present invention. The recorder modules allow data communication with the mobile telephone in such a way that a predefined telephone call is made when the mobile phone is so instructed by the recorder arrangement in order to be able to use it to transmit ECG data with the patient""s data using a suitable data protocol, as well as a data and transmission backup. Only by means of the arrangement or data processing of the, or by the, microcontroller in the signal or data form differing to the nearest knowledge and technology (DE OS 198 48 229) according to the main characteristics of the invention, and by means of a special data protocol, is it possible to carry out a multi-channel ECG transmission by means of data compression of the individual channels, which also results in shorter transmission times. The aforementioned nearest knowledge and technology is not aware of this resource-effect relationship. Here ECG data is sent from the A/D converter directly to the RAM memory and in turn from here directly to the mobile phone unit. As a result, a data-compressing treatment/control of this data is not possible. Compared to the arrangement of the aforementioned nearest knowledge and technology, this invention produces advantageous effects of such proportions that in the case of the solution in accordance with the invention as described here data is compressed by the microcontroller before it is sent to the mobile phone, which reduces the transmission time approximately by a factor of 5 compared to non-compressed transmission, and that according to this technical theory in accordance with the invention a theoretically unlimited number of individual ECG channels can be transmitted, even if the data quantities in the individual channels differ from one another due to the various degrees of compression which are possible. In contrast to the nearest knowledge and technology, this technical theory uses in accordance with the invention a memory card employing flash technology (flash card) for recording data. This method of storage also allows data to be stored for 24 or 48 hours when used in conjunction with transmission by telephone, or it permits the storage of a very large number of short-term individual events. It is therefore also possible in a second mode to xe2x80x9cStore Onlyxe2x80x9d the short or long-term ECG, thereby creating a new operating mode for the long-term ECG and event recording methods. Furthermore the technical theory enables the permanent storage of data using a flash card even when the battery is changed or its power reserves are absolutely exhausted. This allows recorded data to be transmitted over a mobile phone at any time in the future, and no data loss occurs even when the battery is changed in the meantime. Finally, the flash card with the stored data employed in accordance with the invention can be removed from the recorder and read into a PC at another location. This expands the application possibilities when storing large quantities of data. It is not absolutely necessary to read out data via the serial interface. The technical solution in accordance with the invention therefore has the advantage of 3 methods, namely:
event recording in loop mode, including storage of the case history with the option of being able to transmit data immediately via mobile phone in case of emergency,
event storage for subsequent evaluation, as well as
complete, continuous long-term ECG storage over a period of several days. To record an event it is only necessary to trigger recording by pressing one key; the following processes take place fully automatically.
Transmittance of ECG data in the event of critical pulse irregularities takes place automatically and safely by means of a special software. The threshold switches as specified in the current knowledge and technology are only able to detect simple pulse rhythm irregularities, which puts the medical value or the required safety of the patient in question.

Method for recording and transmitting a multi-channel ECG and an arrangement as a portable recorder for carrying out this procedure

Abstract: The invention concerns a method for recording and transmitting a multi-channel ECG and an arrangement as a portable recorder for carrying out the procedure as part of a telemedical system (ECGxe2x80x94recorderxe2x80x94mobile telephonexe2x80x94evaluation centre).

Abstract: The purpose of the invention is to enable automatic transmission of the recorded ECG in any length using a conventional, mobile radio controlled telephone.

Abstract: The invention fulfils this purpose in that following a multi-channel amplification (2) A/D conversion (3) and processing by a pacemaker controller (10) takes place and both are passed on to a microcontroller (4) for further processing and storage with subsequent transmittance via a serial interface (7) to an aforementioned mobile telephone (8) or a PC (9). In addition a removable flash card (6) is also allowed for, by means of which, for example, data can be read in at another location.


A human UDP galactose-4-epimerase polypeptide and DNA (RNA) encoding such polypeptide and a procedure for producing such polypeptide by recombinant techniques is disclosed. Also disclosed are methods for utilizing such polypeptide for the treatment of galactosemia. Also disclosed are diagnostic assays for the detection of mutations in the nucleic acid sequencing encoding human UDP galactose-4-epimerase protein and for detecting an altered level of human UDP galactose-4-epimerase protein in a sample derived from a host.

Carbohydrates are major sources of energy in animals, plants and many microorganisms. They can also be precursors in the biosynthesis of other compounds, such as fatty acids, triglycerides, and some amino acids. Carbohydrates are also important as structural components of connective tissue, nervous tissue, bacterial cell walls, and nucleic acids.
Disaccharides ingested by higher animals are usually hydrolyzed to their monosaccharide components before absorption into the intestine. For example, sucrose is converted into glucose and fructose, maltose is converted into glucose, and lactose is converted into glucose and galactose in most cases by enzymatic activity. It is these monosaccharides that are eventually used for the biosynthesis of carbohydrates. The L forms of the monosaccharides are of small consequence and it is the D form which are most often utilized in the biosynthesis of carbohydrates.
Galactose is an important precursor in carbohydrate biosynthesis and the synthesis of many other macromolecules which are vital to the normal functioning of a mammalian system.
Uridine diphosphate-galactose (UDP-galactose)is also an important intermediate in the metabolism of free D-galactose, formed by the enzymatic hydrolysis of lactose or milk sugar in the intestinal tract. D-galactose is converted into D-glucose in the liver by two series of reactions which have attracted much attention because they are subject to genetic defects in man, resulting in different forms of the hereditary disease galactosemia. Galactosemia results from three known forms of deficiency, galactokinase deficiency, galactose-1-phosphate uridyltransferase deficiency and UDP-galactose-4-epimerase deficiency.
In the liver, free D-galactose is first phosphorylated at carbon atom 1 by galactokinase, to yield D-galactose-1-phosphate, which is converted into UDP-galactose by one of two possible reactions. The minor route is catalyzed by UTP galactose-1-phosphate uridyltransferase.
The UDP-galactose so formed is normally converted into UDP glucose by UDP-galactose-4-epimerase. These reactions make it possible for the galactose residue to enter into the main pathways of glucose metabolism, since UDP-glucose, as we shall see, can donate its glucose residue to glycogen. This uridyltransferase is present in high amounts in the liver of adults but lacking in infants.
The second pathway for utilization of free galactose also begins with galactose 1-phosphate. It is catalyzed by UDP-glucose: galactose 1-phosphate uridyltransferase. This particular enzyme is present in normal fetal liver but is lacking in infants with one form of galactosemia. Such infants are thus unable to utilize galactose by either pathway. Galactosemic infants have an excessively high concentration of D-galactose in the blood and suffer from cataracts of the lens of the eye, mental disorders, impairment of the peripheral nervous system, blindness, hearing deficiency, organomegaly, deranged liver function, including elevated blood galactose, galactosuria, hyper-cholbremic acidosis, albuminuria and aminoaciduria (Mason, H. H. and Turner, M. E., Am. J. Dis. Child, 50:359 (1935) and Komrower, G. M. et al., Arch. Dis. Child, 31:254 (1956)).
Mental retardation is the most significant outcome of galactosemia. The extent of retardation is characterized in that extremely low IQ values result. Psychological problems also seem to be prevalent, with inadequate drive, shyness and withdrawal (Nadler, H. L., et al., Galactosemia, Springfield, Ill., Charles C. Thomas, p. 127 (1969) and Komrower, G. M. and Lee D. H., Arch. Dis. Child, 45:367 (1970)). Other results include a high incidence of ovarian failure with hypergonadotrophic hypogonadism in females who have had adequate dietary therapy (Kaufman, F. R. et al., N. Engl. J. Med., 305:994 (1981); Steinmann, B. et al., N. Engl. J. Med., 305:464 (1981); Kaufman, F. R., et al., J. Inherited Metab. Dis., 9:140 (1986); Robinson, A. C. R., et al., Br. J. Obstet. Gynaecol., 91:199 (1984); and Fraser, I. S., et al., Clin. Reprod. Fertil., 4:133 (1986)). These deficiencies are only a few of the deficiencies which result from this disease and there are numerous other disorders and anatomical and biological problems which result from this disease. The second type of galactosemia is similar to the first type with minor variations in the biological causes and resulting diseases.
Uridine diphosphate galactose-4-epimerase is the third enzyme in the metabolism of dietary galactose and the key enzyme in de novo synthesis of galactose metabolites from glucose (Gitzelmann, R., and Steinmann, B., Enzyme, 32:37-46, (1984)). UDP galactose-4-epimerase catalyzes a reversible transaction between UDP-glucose and UDP-galactose, and a deficiency of this enzyme results in galactosemia.
The first case of epimerase deficiency was documented in 1972 by Gitzelmann in the blood cells of an apparently healthy infant (Gitzelmann, R., Helv. Paediat. Acta, 27:125-130 (1972)). Subsequent clinical findings indicated that severe clinical manifestations of galactosemia were usually observed in patients with generalized epimerase deficiency and were indistinguishable from the classic galactosemia caused by galactose-1-phosphate uridyltransferase deficiency (Henderson, M. J., and Holton, J. B., J. Inher. Metab. Dis., 6:17-20 (1983)). The incidence of complete absence of epimerase activity in circulating blood cells in estimated to be 1 in 23,000 in Japan (Misumi, H. et al., Clinica Chimica Acta, 116:101-105 (1981)). Somatic cell hybrid studies have defined an area from chromosome 1 pter-p21 that likely contains a gene for galactose epimerase (Benn, P. A. et al., Cytogenet. Cell Genet., 24:138-142 (1979) and Lin, M. S. et al., Cytogenet. Cell Genet., 24:217-223 (1979)).
Galactosemia in general is inherited as an autosomal recessive trait. Also, the enzyme may be present, but non-functional due to a mutation in the gene sequence encoding the functional enzyme.
The gene of the present invention has been putatively identified as a human UDP-galactose-4-epimerase. This identification has been made as a result of amino acid sequence homology to the rat galE MRNA for UDP-galactose-4-epimerase.
In accordance with one aspect of the present invention, there are provided novel mature polypeptides as well as biologically active and diagnostically or therapeutically useful fragments, analogs and derivatives thereof.
In accordance with another aspect of the present invention, there are provided isolated nucleic acid molecules encoding the polypeptide of the present invention, including mRNAs, DNAS, cDNAs, genomic DNAs as well as analogs and biologically active and diagnostically or therapeutically useful fragments thereof.
In accordance with yet a further aspect of the present invention, there are provided processes for producing such polypeptides by recombinant techniques comprising culturing recombinant prokaryotic and/or eukaryotic host cells, containing a nucleic acid sequence encoding the polypeptide of the present invention under conditions promoting expression of said protein and subsequent recovery of said protein.
In accordance with yet a further aspect of the present invention, there is provided a process for utilizing such polypeptide, or polynucleotide encoding such polypeptide for therapeutic purposes, for example, to treat galactosemia, cataracts, mental disorders, impairment of the peripheral nervous system, blindness, hearing deficiency and organomegaly.
In accordance with yet a further aspect of the present invention, there are also provided nucleic acid probes comprising nucleic acid molecules of sufficient length to specifically hybridize to the polypeptide of the present invention.
In accordance with yet a further aspect of the present invention, there are provided antibodies against such polypeptides.
This invention also provides a method to diagnose human UDP galactose-4-epimerase deficiency which comprises isolating a nucleic acid sample from an individual and assaying the sequence of said nucleic acid sample with the referenced gene of the invention and comparing differences between said sample and the nucleic acid of the instant invention, wherein said differences indicate mutations in the human UDP galactose-4-epimerase gene isolated from an individual.
This invention also provides a method for treating conditions which are related to insufficient human UDP galactose-4-epimerase activity via gene therapy. An additional reference gene comprising the UDP galactose-4-epimerase gene of the instant invention is inserted into a patient""s cells either in vivo or ex vivo. The referenced gene is expressed in transfected cells and as a result, the protein encoded by the referenced gene corrects the defect thus permitting the transfected cells to function normally and alleviate disease conditions (or symptoms).
In accordance with yet a further aspect of the present invention, there are provided processes for utilizing such polypeptides, or polynucleotides encoding such polypeptides, for in vitro purposes related to scientific research, synthesis of DNA, manufacture of DNA vectors and the treatment and diagnosis of human disease.
These and other aspects of the present invention should be apparent to those skilled in the art from the teachings herein.
The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims.

Human uridine disphosphate galactose-4-epimerase


A method of producing an extruded, powdered/granulated composition comprising an active pharmaceutical ingredient (API), by the steps of providing an API and a porous inorganic excipient, and processing them by an extrusion process to directly produce an extruded, powdered/granulated composition wherein the API is at least partially absorbed within the pores of the inorganic excipient. In preferred embodiments, the API is melted, or solubilised in a solubilizer.

Hot-melt extrusion (HME) has been used in a wide range of manufacturing processes. Aside from its use in the plastics, rubber and food manufacturing sectors, HME has been used in the manufacture of pharmaceutical dosage forms e.g. tablets or films. In general terms, HME involves pumping a mixture of raw materials at controlled (often elevated) temperature and/or pressure through a barrel to produce a composition that is forced out of the barrel through a die. The raw materials are typically fed into the extruder (the extruder barrel) via a hopper. Flow through the barrel is usually associated with mixing, grinding, compressing, kneading and/or venting. Within the barrel are typically one or two rotating screws (corotating or counter rotating).
Initial extruded compositions (extrudates) usually require further down steaming processing before final use, for example into powders for tabletisation, e.g. tablet compression, in the field of pharmaceuticals. However, many prior art extrusion methods (especially where Ibuprofen is extruded) result in sticky extrudates that require cryo-milling for powder formation. Cryo-milling is a time consuming and costly processing step that inhibits the scale-up of such processes to an industrial operation. Other resource-consuming, post-extrusion processing steps can include cooling, cutting, pelletising and micronisation.
It is amongst the objects of the present invention to attempt a solution to this problem (i.e. to improve the speed and efficiency with which a powdered/granulated extrudate can be formed), and to improve various characteristics of extrudates (and pharmaceutical form derived therefrom) for pharmaceutical use, such as improved drug-loading, stability and taste-masking and, in the case of tablet forms in particular, increased disintegration rate, increased hardness and decreased friability.

Method of producing a granulated composition